A TEXTBOOK OF POSTPARTUM HEMORRHAGE - PART 6 pptx

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(vWF:RCo) and collagen-binding assay

(vWF:CB), accompanied by variable reductions

in vWF antigen (vWF:Ag) and FVIII Several

further tests that aid in classification include

analysis of ristocetin-induced platelet

aggrega-tion (RIPA), vWF multimer and assay of FVIII

binding to vWF63 The diagnosis may not be

straightforward, as one or more of the activities

of FVIII and vWF may be borderline and even

normal It is often necessary to repeat the

estimations on at least three occasions Stress,

physical exercise, recent surgery and pregnancy

all increase plasma vWF levels and FVIII levels,

and diagnosis may be difficult in these

circum-stances64 When investigating patients with

bor-derline results, it should be taken into account

that FVIII and vWF levels are 15–20% lower in

individuals with blood group O compared to

individuals with blood group A64

The aim of therapy for vWD is to correct

the impaired primary hemostasis and impaired

coagulation Treatment choice depends on the

severity and the type of disease, and on the

clinical setting Treatment options usually

include DDAVP and vWF-containing blood

products65

DDAVP, a synthetic vasopressin analogue,

releases vWF from endothelial stores; there is

also an increase in the plasma FVIII level It is

usually given by slow intravenous infusion of

0.3µg/kg over 20 min, which can be repeated

every 4–6 h on two or three occasions The drug

can also be given subcutaneously or as a nasal

spray Side-effects include hypotension, facial

flushing, fluid retention for up to 24 h and

con-sequent hyponatremia DDAVP can safely be

used during pregnancy66and after delivery It is

effective in securing in many situations in type 1

vWD with a 3–5-fold increase in the plasma

vWF and FVIII levels It is of no therapeutic

benefit in type 3 vWD because of the very low

basal levels of vWF and FVIII The response in

types 2 is less predictable DDAVP is

contrain-dicated in patients with type 2B because it may

exacerbate the coexisting thrombocytopenia

Patients should have a test of DDAVP (if

possible when not pregnant) to see if it is

effective in their individual case

Plasma-derived vWF concentrates are

neces-sary in patients who do not respond adequately

to DDAVP or in whom it is contraindicated

The loading dose is 40–60 IU/kg, and thiscan be followed by repeat doses every 12–24 h

to maintain vWF activity (vWF:RCoF) > 50%.All currently available concentrates are derivedfrom plasma As at least one viral inactivationstep is included in their manufacture, they areunlikely to transmit hepatitis or HIV, but there

is still a risk of parvovirus infection

von Willebrand disease and pregnancy

von Willebrand disease is the most commoncongenital hemostatic disorder in pregnancy In

a normal pregnancy, both FVIII and vWF levelsprogressively increase (Figure 2)67 vWF starts

to rise as early as the 6th week and by the thirdtrimester may have increased three- to fourfold.FVIII and vWF levels also increase in mostwomen with vWD, which may explain the fre-quent improvement in minor bleeding manifes-tations during pregnancy The hemostaticresponse to pregnancy depends on both the typeand severity of disease Most women with type 1vWD have an increase in FVIII and vWF levelsinto the normal non-pregnant range, which maymask the diagnosis during pregnancy However,levels may remain low in severe cases FVIII andvWF antigen levels often increase in pregnantwomen with type 2 vWD with minimal or

no increase in vWF activity levels In type 2BvWD, the increase in the abnormal vWF cancause progressive and severe thrombocytopenia,but intervention is not usually required Mostwomen with type 3 vWD have no improvement

in FVIII or vWF levels during pregnancy68.After delivery, FVIII and vWF in normalwomen fall slowly to baseline levels over aperiod of 4–6 weeks However, the postpartumdecline of these factors may be rapid and signifi-cant in women with vWD68 As the individualhemostatic response to pregnancy is variable,vWF and FVIII levels should be monitoredduring pregnancy and 3–4 weeks after delivery.Antepartum hemorrhage is uncommon inwomen with vWD, but may occur after sponta-neous miscarriage or elective termination,occasionally as the initial presentation of vWD.Women with vWD are at substantial risk forsecondary postpartum hemorrhage, especially3–5 days after delivery vWD may also exacer-bate bleeding due to other obstetric causes, such

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as uterine atony or a trauma to the birth canal.

Other pregnancy-associated reasons for

bleed-ing in women with vWD include extensive

bruising and hematomas at intramuscular

injection, episiotomy and surgical wound sites

For patients whose vWD profile has

normal-ized in pregnancy, no specific hemostatic

sup-port is required Regional analgesia may

proceed in these patients after discussion with

an obstetric anesthetist Although neonatal

bleeding is rare, ventouse delivery and

high-cavity forceps should be avoided Careful and

prompt repair of episiotomy wounds or perineal

tears is advisable

For patients whose vWF activity (vWF:RCo)

has not normalized, decisions about regional

analgesia should be individualized69

Hemo-static supportive therapy with DDAVP or vWF

concentrate should be given to cover delivery or

Cesarean section if the FVIII level is less than

50% or if vWF:RCo has not normalized66

Because of the high incidence of secondary

postpartum hemorrhage in patients with vWD,

efforts should be made to ensure that placenta is

complete upon expulsion or removal

After delivery, all patients should be closely

observed for postpartum hemorrhage and

uncorrected hemostatic defects treated In

responsive patients, DDAVP is the treatment of

choice to prevent and treat mild to moderate

postpartum bleeding70 FVIII and vWF:RCo

should be checked a few days postpartum

because they may fall rapidly after delivery

FVIII and vWF:RCo should be maintained inthe normal range for at least 3–7 days afterCesarean section It is difficult and unnecessary

to diagnose vWD in the neonate, except whentype 3 vWD is suspected Generally, diagnosiscan be postponed until later in childhood

HEMOPHILIAS

Hemophilias A and B are the most commonsevere congenital bleeding disorders associatedwith reduced or absent coagulation FVIII andFIX, respectively The incidence of hemophilia

A is around 1 in 10 000 live male births philia B is about five times less common thanhemophilia A The genes for both conditionsare located on the X-chromosome; they aretherefore sex-linked disorders that almost exclu-sively affect males Clinically, the hemophiliashave an identical presentation and can only bedistinguished by measuring plasma levels of thespecific clotting factors The clinical severity isdirectly related to plasma concentrations ofFVIII/FIX Individuals with levels of below 1%

Hemo-of normal have severe hemophilia and the mostfrequent bleeds Females in families with a his-tory of hemophilia may be obligate, potential orsporadic carriers, depending on the details ofthe pedigree71 An obligate carrier is a womanwhose father has hemophilia, or a woman whohas family history of hemophilia and who hasgiven birth to a hemophiliac son, or a womanwho has more than one child with hemophilia

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050100150200250300350400450

Weeks gestation

FVIIIvWF:Ag

Figure 2 Levels of factor VIII and vWF in normal pregnancy From Giangrande PL Management of

pregnancy in carriers of haemophilia Haemophilia 1998;4:779–84

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A potential carrier of hemophilia is a woman

who has a maternal relative with the disorder A

woman with one affected child and no family

history may be a sporadic carrier71 Female

car-riers of hemophilia may have reduced FVIII/IX

levels because of random inactivation of the

X-chromosome (lyonization) If the FVIII/IX

level is less than 50%, abnormal bleeding may

occur after trauma or surgery

There are two main risks for a female carrier

of hemophilia in pregnancy First, women with

a low FVIII/IX level may be at risk of bleeding

after delivery or during invasive procedures

in the first trimester Second, there is a 50%

chance of each son inheriting hemophilia and

50% of her daughters being carriers

As discussed earlier, the levels of FVIII and

vWF rise during normal pregnancy (Figure 2)

The increase is particularly marked during the

third trimester, when levels of FVIII may rise to

double that of the normal baseline value

Simi-larly, the vast majority of carriers of hemophilia

A will have increased their FVIII production to

within the normal range by late gestation; factor

replacement therapy is thus only rarely required

during pregnancy in carriers of hemophilia A

By contrast, the level of FIX does not increase

significantly during pregnancy, and thus a

woman with a low initial baseline FIX is more

likely to require replacement to control bleeding

complications during delivery

All women who are obligate or potential

carriers of hemophilia should be offered genetic

testing and counseling In particular, they

should have their carrier status determined

to allow for the optimal management of

their pregnancies Genetic testing should be

offered when the individual is able to

under-stand the issues concerned (usually at age of

13–15 years) and after having given informed

consent72 In many individuals in the UK with

hemophilia A and B, the causative mutation

has been identified If the mutation within the

family is known, it is straightforward to screen

the potential carrier If, on the other hand, the

mutation is not known, then linkage analysis

using informative genetic polymorphisms may

be possible If neither of these approaches

is suitable, then direct mutation detection

may be possible by sequencing the FVIII/FIX

gene

Coagulation studies should also be carriedout to identify carriers with low FVIII/FIX lev-els Phenotypic data may be helpful in assessingthe statistical risk of carrriership if moleculardiagnosis is not possible However, normal lev-els of FVIII/FIX do not exclude carriership72.Women who have low levels of FVIII may have

a useful hemostatic response to DDAVP Toestablish whether this response is occurring, atrial of intravenous DDAVP can be attempted,with measurement of the response in FVIIIlevels over the next 24 h

Once carriership has been established,women should be offered prepregnancy coun-seling to provide them with the information nec-essary to make informed reproductive choices

A new technique of preimplantation diagnosis

is potentially useful for carriers of hemophiliawho, after counseling, do not wish to contem-plate bringing up a hemophilic child, but would

not consider termination Following in vitro

fertilization (IVF) treatment, it is possible toremove a single embryonic cell at the 8–16-cellstage and carry out genetic diagnosis Female orunaffected male embryos can then be trans-ferred into the uterus In the UK, each such testrequires a license from the Human Fertilizationand Embryology Authority

If prenatal diagnosis is requested, testing

is usually carried out by chorionic villus pling (CVS) at 11–12 weeks’ gestation; DNAextracted from fetal cells is analyzed The prin-cipal advantage of this procedure is that it may

sam-be applied during the first trimester, so that, iftermination of the pregnancy is required, this

is easier to carry out The main adverse eventrelated to CVS is miscarriage, which is esti-mated at about 1–2% Fetal cells are karyotyped

so that the fetal sex is established If the fetus isfemale, no further tests are done If the fetus ismale, additional tests are conducted to establishwhether the affected gene has been inherited.Cells for karyotyping and as a source of DNAcan also be obtained from amniotic fluid(amniocentesis) after 15 weeks’ gestation; here,the miscarriage rate is about 0.5–1% Fetoscopy

to allow for fetal blood sampling is rarely formed; it can only be performed after about 16weeks’ gestation and has a substantial risk offetal death (1–6%) The use of prenatal diag-nosis is decreasing in developed countries As

per-225

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hemophilia care improves, more couples are

willing to contemplate bringing up a child with

hemophilia67 When prenatal diagnosis has not

been carried out but there is a risk that the child

may have hemophilia, fetal sex should be

diag-nosed by ultrasonography67 This information is

necessary for the obstetrician even if the parents

do not wish to know the sex of the infant

Factor VIII/IX levels in female carriers of

hemophilia should be monitored regularly in

pregnancy It is particularly important to

mea-sure coagulation factor levels toward the end of

the third trimester (34–36 weeks) to plan

man-agement of delivery67 If maternal FVIII/FIX

levels remain low at 34–36 weeks in hemophilia

carriers, treatment is necessary for delivery67 A

FVIII/FIX plasma level of 40% is safe for

vagi-nal delivery, and a level of 50% or greater is safe

for Cesarean section Epidural anesthesia may

be used if coagulation defects have been

cor-rected67 Recombinant FVIII/FIX or DDAVP

(for carriers of hemophilia A only) should

be used Plasma-derived factor concentrate

products, including those subjected to

dual-inactivation processes, have the potential to

transmit non-lipid coated viruses, e.g

parvo-virus, and should not be used Infection of the

fetus with parvovirus may result in hydrops

fetalis and fetal death

If the fetus is a known hemophiliac, is male

and of unknown hemophilia status, or is of

unknown sex, care should be taken to avoid

traumatic vaginal delivery Routine Cesarean

delivery is unnecessary67, but should be carried

out if obstetric complications are anticipated

Most bleeding problems in carriers of

hemo-philia occur postpartum Replacement therapy

should be given immediately after delivery to

mothers with uncorrected hemostatic defect

Treatment options at this stage are the same

as those during labor and delivery Supportive

therapy to maintain hemostasis should be

continued for 3–4 days after vaginal delivery

and for 5–10 days after Cesarean section73

In the infant, intramuscular injections should

be avoided until hemophilia has been excluded

Cord blood should be obtained for FVIII/FIX

assays74 Routine administration of coagulation

factor concentrates to neonates with hemophilia

is unnecessary if delivery has been atraumatic

and there are no clinical signs of hemorrhage74

RARE COAGULATION DISORDERS Fibrinogen deficiency

The hypo- and dysfibrinogenemias comprise

a collection of disorders that are usuallydominantly inherited and associated with bothbleeding and venous thrombotic manifestations.Women are at risk of recurrent miscarriage, andboth antenatal and postnatal hemorrhage Inhypofibrinogenemia, both antigenic and func-tional fibrinogen levels are reduced Thediagnosis of dysfibrinogenemia is made bydemonstrating a prolonged TT with a normalantigenic fibrinogen level

Prophylaxis with fibrinogen concentratesimproves pregnancy outcome and preventsantepartum and postpartum hemorrhage inwomen with hypo- and dysfibrinogenemia.Cryoprecipitate is a good source of fibrinogenbut should not usually be used, as it is not virallyinactivated Its use may be considered in anemergency situation if no other alternatives areavailable The half-life of infused fibrinogen is3–5 days, and treatment is unlikely to be neededmore often than on alternate days Levels above1.5 g/l are required toward the end of pregnancyand at the time of delivery75

Factor VII deficiency

Congenital FVII deficiency is the most common

of the rare inherited coagulation disorders with

an estimated prevalence of 1 in 500 000 It isinherited in an autosomal recessive manner andits frequency is significantly increased in coun-tries where there are consanguineous marriages.FVII levels are usually less than 10% in homo-zygotes and around 50% in heterozygotes.Although there is a poor correlation betweenFVII levels and bleeding risk, hemorrhagesoccur in patients with factor VII levels below10–15%76 Individuals with a moderate FVIIdeficiency often bleed from the mucousmembranes, and epistaxis, bleeding gums andmenorrhagia are common In severe FVII defi-ciency (FVII level < 2%), bleeding into the cen-tral nervous system very early in life leads to ahigh morbidity and mortality Congenital FVIIdeficiency is usually suspected when an isolatedprolongation of the PT is found in a patient

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without liver disease, and a normal APTT and

fibrinogen level

The FVII level may increase up to four-fold

during normal pregnancy76 However, it is

unknown whether FVII levels increase to the

same degree in pregnant women with congenital

FVII deficiency as they do in normal

preg-nancy77 FVII deficiency during pregnancy is a

risk factor for postpartum hemorrhage

Bleed-ing may occur from the placental implantation

site, episiotomies, lacerations to the birth canal,

or surgical trauma occurring with Cesarean

delivery78

Recombinant activated FVII (rFVIIa) has

been approved in the European Union for use in

congenital FVII deficiency79 In places where

this product is not available, fresh frozen

plasma, prothrombin complex concentrates

(PCCs) or plasma-derived FVII concentrate

may be used Because the patient may

poten-tially need a Cesarean delivery and because

peri-neal trauma cannot be anticipated, prophylaxis

is usually recommended at the time of

deliv-ery78 Recombinant FVIIa has been given as an

initial bolus injection of 20–50µg/kg, followed

by further boluses of 10–35µg/kg every 4–6

hours to cover vaginal delivery or Cesarean

section in patients with congenital FVII

defi-ciency78,80 It has also been used as an initial

bolus injection of 13µg/kg with subsequent

continuous infusion at 1.7–3.3µg/kg/h for 4

days76(see Chapter 26)

Factor X deficiency

Congenital FX deficiency is an autosomal

recessive disorder The prevalence of the severe

(homozygous) form is 1 : 1 000 000 in the

gen-eral population and is much higher in countries

where consanguineous marriages are more

common The prevalence of heterozygous FX

deficiency is about 1 : 500, but individuals

are usually clinically asymptomatic Severe FX

deficiency (FX level < 1%) is associated with a

significant risk of intracranial hemorrhage in the

first weeks of life and umbilical stump bleeding

The most frequent symptom is epistaxis, which

is seen with all severities of deficiency

Menorrhagia occurs in half of the women

Severe arthropathy may occur as a result of

recurrent joint bleeds Mild deficiency is

defined by FX levels of 6–10%; these als are often diagnosed incidentally but mayexperience easy bruising or menorrhagia Thediagnosis of FX deficiency is suspected follow-ing the finding of a prolonged APTT and PTand is confirmed by measuring plasma FX levels.Thirteen pregnancies in eight patients withisolated FX deficiency have been reported inthe literature81 The complications describedinclude spontaneous abortions, placentalabruptions, premature births and postpartumhemorrhage FX levels increase during preg-nancy and antenatal replacement therapy is notusually needed However, women with severe

individu-FX deficiency and a history of adverse outcome

in pregnancy may benefit from aggressivereplacement therapy75 As the half-life of FX

is 24–40 h, a single daily infusion is usuallyadequate FX levels of 10–20% are generallysufficient for hemostasis75 and are required atthe time of delivery

FX is present in intermediate-purity FIX centrates (prothrombin complex concentrates,PCCs) FX levels should be monitored as cau-tion is required because of the prothromboticproperties of these concentrates Fresh frozenplasma may be an alternative when prothrombincomplex concentrates are not available

con-Combined deficiencies of the vitamin K-dependent factors II, VII, IX and X

Congenital combined deficiency of factors II,VII, IX and X is an autosomal recessive bleed-ing disorder It is caused by deficiency ofenzymes associated with vitamin K metabolism(e.g γ-glutamyl carboxylase) as a result ofhomozygous genetic mutations Muco-cutaneous and postoperative related bleedinghave been reported Severe cases may presentwith intracranial hemorrhage or umbilical cordbleeding in infancy Some individuals haveassociated skeletal abnormalities (probablyrelated to abnormalities in bone vitaminK-dependent proteins such as osteocalcin).Severe bleeding is usually associated withactivities of the vitamin K-dependent factors of

< 5% Affected individuals show prolongation

of the APTT and PT associated with variablereductions in the specific activities of factors II,VII, IX and X

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The clinical picture and response to vitamin

K is variable, some responding to low-dose oral

vitamin K but others are non-responsive even to

high-dose intravenous replacement In those

individuals who are non-responsive to vitamin

K, prothrombin complex concentrates are the

product of choice

There is a single report of a pregnancy

pro-gressing to term in an individual with severe

congenital vitamin K-dependent clotting factor

deficiency managed with oral vitamin K 15 mg

daily throughout pregnancy Bleeding from an

episiotomy wound in this case required fresh

frozen plasma82

Factor XI deficiency

FXI deficiency is an autosomally inherited

con-dition, which is particularly common in

Ashke-nazi Jews in whom heterozygote frequency is

8% Overall, the prevalence of severe deficiency

is approximately 1 : 1 000 000 but partial

defi-ciency is much more common FXI defidefi-ciency is

unlike most of the other rare coagulation

disor-ders in that heterozygotes may have a significant

bleeding tendency that is poorly predicted

by the FXI level Spontaneous bleeding is

extremely rare, even in those with undetectable

FXI levels Bleeding is provoked by injury or

surgery, particularly in areas of high fibrinolytic

activity (e.g genitourinary tract) Menorrhagia

is common, and women with FXI deficiency

may be diagnosed as a consequence of this FXI

deficiency rarely results in bleeding during

pregnancy, but women with severe or partial

deficiency may suffer postpartum bleeding75

The APTT is usually prolonged and

diag-nosis is confirmed by finding a low FXI level

The deficiency is classified as severe if the FXI

level is less than 15% and partial at 15–70%; the

lower limit of the normal range is 70% There is

controversy about changes in FXI levels during

normal pregnancy, some studies demonstrating

an increase and others a decrease83 Changes

in FXI levels in women with FXI deficiency

have been inconsistent during pregnancy84 It is

therefore recommended that FXI levels should

be checked at the initial visit, and during the

third trimester in FXI-deficient women

In women with partial FXI deficiency and

no bleeding history but previous hemostatic

challenge, treatment is not usually requiredduring vaginal delivery In women with partialdeficiency and significant bleeding history or noprevious hemostatic challenges, tranexamic acid

is often used for 3 days, with the first dose beingadministered during labor Tranexamic acid isalso used to manage prolonged mild intermit-tent secondary postpartum hemorrhage which

is a common presentation of FXI-deficientpatients84 FXI concentrate is needed forseverely deficient women to cover vaginaldelivery and also for Cesarean section The aim

is to maintain the FXI level > 50% during laborand for 3–4 days after vaginal delivery and 7days after Cesarean section FXI concentrate ispotentially thrombogenic; the single doseshould not exceed 30 IU/kg with the aim ofraising FXI level to no greater than 70%84.Concurrent use of tranexamic acid or otherantifibrinolytic drugs with FXI concentrateshould be avoided Fresh frozen plasma can beused, but, in patients with severe deficiency, it isdifficult to produce a sufficient rise (to morethan 30%) without the risk of fluid overload75.Recombinant FVIIa has been used successfully

to manage adult patients with FXI deficiencyundergoing surgery, although it is not licensedfor this indication75

Factor XIII deficiency

Congenital FXIII (fibrin stabilizing factor)deficiency is an autosomal recessive disorder

It is characterized by features of delayedand impaired wound healing with bleedingoccurring 24–36 h after surgery or trauma.Umbilical bleeding in the first few weeks of life

is very suggestive of the disorder Soft tissuebleeds are more common than hemarthroses,which usually only occur after trauma Sponta-neous intracranial bleeds are a characteristicfeature Spontaneous abortions occur in earlypregnancy because FXIII is required forsuccessful implantation Women with FXIIIdeficiency are also at increased risk of postnatalbleeding75 The severity of the bleeding statevaries markedly between individuals with appar-ently similar FXIII plasma levels The routinetests (APTT and PT) are normal and the FXIIIlevel has to be specifically requested of thelaboratory

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FXIII has a half-life of 7–10 days and

there-fore only needs to be given at 4–6-weekly

inter-vals to maintain a level > 3% which is necessary

to prevent spontaneous intracranial bleeds Up

to 50% of severely (FXIII level < 1%) affected

women may miscarry without appropriate FXIII

treatment75 All severely affected individuals

should be started on monthly infusions of

plasma derived FXIII concentrate from the time of

diag-nosis to prevent intracranial bleeds and these

should be continued during pregnancy75 FXIII

levels fall throughout pregnancy and should be

monitored, aiming to keep the trough level > 3%

FXIII deficiency may also cause

life-threatening hemorrhage in the neonate with

levels < 3% The disorder can be diagnosed

from cord or peripheral blood samples

Treat-ment of an acute bleeding episode is with FXIII

concentrate at a dose of 20 IU/kg75

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44 Moscardo F, Perez F, de la Rubia J, et al.

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45 Zupancic Salek S, Sokolic V, Viskovic T, et al.

Successful use of recombinant factor VIIa formassive bleeding after caesarean section due

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46 Ludlam CA The evidence behind inhibitor

treatment with recombinant factor VIIa physiol Haemost Thromb 2002;32(Suppl 1):13–18

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51 Porteous AO, Appleton DS, Hoveyda F, Lees

CC Acquired haemophilia and postpartum

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52 Boggio LN, Green D Acquired hemophilia Rev

Clin Exp Hematol 2001;5:389–404

53 Bates SM, Ginsberg JS How we manage venous

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54 Bates SM, Greer IA, Hirsh J, Ginsberg JS Use

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Presented at the Seventh ACCP Conference

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55 Ginsberg JS, Hirsh J, Turner C, et al Risks to the

fetus of anticoagulant therapy during pregnancy

Thromb Haemost 1989;61:197–203

56 Vitale N, De Feo M, De Santo LS, et al

Dose-dependent fetal complications of warfarin in

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57 Walker ID In O’Shaughnessy D, Makris M and

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59 Rahimi G, Rellecke S, Mallmann P, Nawroth F

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61 Kale A, Bayhan G, Yalinkaya A, Yayla M

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62 Pajor A, Nemes L, Demeter J May Hegglin

anomaly and pregnancy Eur J Obstet Gynecol

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63 Favaloro EJ Laboratory assessment as a critical

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sub-classification of von Willebrand’s disease

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64 Laffan M, Brown SA, Collins PW, et al The

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from the UKHCDO Haemophilia 2004;10:

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65 Pasi KJ, Collins PW, Keeling DM, et al.

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66 Mannucci PM How I treat patients with von

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Investi-gation and management of haemorrhagic

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74 Kulkarni R, Lusher JM, Henry RC, Kallen DJ.Current practices regarding newborn intracranialhaemorrhage and obstetrical care and mode ofdelivery of pregnant haemophilia carriers: a

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76 Jimenez-Yuste V, Villar A, Morado M, et al.

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77 Fadel HE, Krauss JS Factor VII deficiency and

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78 Eskandari N, Feldman N, Greenspoon JS.Factor VII deficiency in pregnancy treated with

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factor VII deficiency: therapy with recombinant

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80 Muleo G, Santoro R, Iannaccaro PG, et al.

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congenital and acquired factor VII deficiencies

Blood Coagul Fibrinolysis 1998;9:389–90

81 Romagnolo C, Burati S, Ciaffoni S, et al Severe

factor X deficiency in pregnancy: case report and

review of the literature Haemophilia 2004;10:

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82 McMahon MJ, James AH Combined deficiency

of factors II, VII, IX, and X (Borgschulte–

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83 David AL, Paterson-Brown S, Letsky EA Factor

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84 Kadir RA, Economides DL, Lee CA Factor XI

deficiency in women Am J Hematol 1999;60:

48–54

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THE USE OF RECOMBINANT FACTOR VIIa

S Sobieszczyk and G H Brfborowicz

INTRODUCTION

As described in detail in other chapters of this

volume, conditions with excessive bleeding, as

are seen with uterine rupture, placenta accreta,

abruption and uterine atony, often require

intensive resuscitation with blood components

and coagulation factors In such circumstances,

blood transfusion may be life-saving, but on

occasion involves exposing the patient to

addi-tional risks Over the years, numerous efforts

have been put forward to reduce these risks

One of the most spectacular is discussed in this

chapter

Recombinant activated factor VII (rFVIIa)

(NovoSeven®; Novo Nordisk A/S, Bagsvaerd,

Denmark) was developed for the treatment of

spontaneous and/or surgical bleeding episodes

in patients with hemophilia A or B with

forma-tion of allo-antibodies to FVIII or FIX after

replacement therapy1–3 rFVIIa is currently

licensed for this indication in most countries

world-wide The US Food and Drug

Adminis-tration (FDA) licensed rFVIIa on March 25,

1999 for bleeding episodes in patients with

hemophilia A or B and inhibitors to FVIII or

FIX The FDA approved use of rFVIIa in 2005

for additional indications such as surgical

proce-dures in patients with hemophilia A or B and

inhibitors, and treatment of bleeding episodes

in patients with factor VII deficiency4 In

Europe, it is also approved for use in bleeding

episodes in patients with acquired hemophilia

due to auto-antibodies against endogenous

FVIII or FIX, surgical procedures in this group

of patients, and Glanzmann’s thrombasthenia

Beyond its currently recognized indications,

rFVIIa has been effectively used ‘off label’ on an

empirical basis as a general hemostatic agent in

a wide range of conditions associated with

acute, uncontrolled, or otherwise profoundbleeding, and in other clinical circumstancesassociated with excessive bleeding in patientswithout pre-existent coagulation defects5,6.Indeed, the early descriptions of the benefits ofrFVIIa in trauma patients7–9were bolstered by acompassionate use study, which suggested thatrFVIIa administration could reverse massivebleeding, and thus significantly decrease trans-fusion requirements observed in critically ill,multi-transfused trauma patients10,11 Recently,rFVIIa was approved for the treatment ofhemorrhage associated with congenitalfactor VII deficiency12,13 and Glanzmann’sthrombasthenia14,15

PECULIARITIES OF OBSTETRIC HEMORRHAGE

Patients who develop massive, life-threateningpostpartum hemorrhage often have a combina-tion of ‘coagulopathic’ diffuse bleeding in addi-tion to ‘surgical bleeding’ Whereas bleedingfrom larger vessels may be controlled bysurgeons using a variety of operations (seeChapters 30–32), the ability to control diffusebleeding is limited and, in many cases, not feasi-ble Thus administration of hemostatic drugsthat can control the coagulopathic component

of blood loss may reduce mortality and ity in such patients Clinical experience pres-ently suggests that rFVIIa is a safe and effectivehemostatic measure in severe obstetric hemor-rhage, both as a adjunctive treatment to surgicalhemostasis as well as a ‘salvage’ or ‘rescue’ ther-apy where postpartum hemorrhage is refractory

morbid-to current pharmaceutical and ‘uterus sparing’surgical techniques The ‘evidence’ behind thepreceding statement comes from three sources:

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(1) Studies on its mechanism of action;

(2) Accumulating reports in the literature; and

(3) Data from clinical studies

All suggest that rFVIIa has the potential to

func-tion as a ‘universal hemostatic agent’16 across a

range of indications characterized by impaired

thrombin generation in non-hemophilic patients,

many of whom are critically ill and refractory to

other hemostatic treatment options

The usual manner for treating postpartum

hemorrhage includes, first,

non-invasive/non-surgical methods, including administration of

crystalloid solutions and/or red blood cells,

uterine massage, uterotonic medications

(oxytocin, ergotamine, prostaglandins), and,

second, invasive/surgical methods, e.g ligation

of uterine vessels, ligation of iliac arteries,

angio-graphic embolism of uterine/iliac arteries, or the

B-Lynch method Unfortunately, the overall

effectiveness of such procedures to arrest

hem-orrhage and prevent the need for emergency

hysterectomy is estimated to be only about

50%17,18 Moreover, comparatively few centers

world-wide have access to the physical

equip-ment or surgical manpower resources necessary

to conduct all the aforementioned procedures

COAGULATION FACTOR VII:

THE HUMAN PROTEIN AND

RECOMBINANT PRODUCT

Structure of the human FVII (hFVII)

Human factor VII (eptacog alpha) is a serine

protease (molecular weight 50 kDa) composed

of 406 amino acid residues, belonging to the

group of vitamin K-dependent coagulation

glycoproteins The primary site of FVII

synthesis in humans is the liver Factor VII

is composed of four discrete domains:

a γ-carboxyglutamic acid (Gla)-containing

domain, two epidermal growth factor

(EGF)-like domains, and a serine protease domain All

appear to be involved, to different extents, in an

optimal interaction with tissue factor (TF) The

Gla domain of factor VII is also essential for

activation of factor X and other macromolecular

substrates The activation of factor VII to factor

VIIa involves the hydrolysis of a single peptide

bond between Arg152 and Ile153 The result is

a two-chain molecule consisting of a light chain

of 152 amino acid residues and a heavy chain

of 254 amino acid residues held together by asingle disulfide bond19,20(Figures 1 and 2)

Production of rFVIIa using recombinant DNA technique

The development of rFVIIa was undertaken toalleviate the problems associated with the use ofplasma-derived factor VIIa, such as limited sup-ply and possible viral contamination Multiplesteps were involved in the development of thisrecombinant protein First, the human gene forfactor VII, located on chromosome 13, com-prising eight exons (coding regions), was iso-lated from the liver gene library After standardamplification procedures used to generate mul-tiple copies of the hFVII gene, it was transfectedinto a baby hamster kidney cell line A mastercell bank of the transfected cell line that secretesfactor VII in a single-chain form into the culturemedium was then established During the laststeps, proteolytic conversion by autocatalysis tothe active two-chain form (rFVIIa) takes place

in a chromatographic purification process,which was shown to remove exogenous viruses

No human serum or other proteins are used inthe production of rFVIIa (see Chapter 15) Theprotein backbone is identical with human puri-fied factor VIIa The final product (rFVIIa),despite minor differences in carbohydratecomposition, is structurally similar to plasma-derived factor VIIa The activity of rFVIIa issimilar to that of natural factor VIIa present inthe body21,22(see Table 1)

Human activated factor VII (hFVIIa) orrecombinant activated factor VII (rFVIIa) is anaturally occurring initiator of hemostasis that

is vital to the coagulation process, as it combineswith tissue factor (TF) at the site of blood vesseldamage in a natural way, stimulates thrombingeneration, permits stable fibrin clot formation,and thereby the cessation of bleeding

PHARMACOKINETIC STUDIES OF rFVIIa IN HUMANS

The pharmacokinetics of single-bolus doses

of rFVIIa have been studied in various adultpopulations: patients with hemophilia, patients

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with cirrhosis, and healthy volunteers The

pharmacokinetic parameter values of rFVIIa

after bolus administration were similar The

elimination half-life (t1/2) ranged from 2.45 to

2.72 h and clearance (CL) ranged from 32.8

to 34.9 ml/h.kg23 Lindley and colleagues

investigated the single-dose pharmacokinetics

of rFVIIa, evaluated in three dose levels (17.5,

35.0, 70µg/kg) in hemophilic A/B patients with

inhibitors The results of these investigations

demonstrate that the mean t1/2of recombinant

factor VIIa is independent of dose level24

Pharmacokinetic evaluations suggest the

elimination of rFVIIa follows linear kinetics

with a faster clearance rate and shorter t1/2when

rFVIIa is administered for bleeding episodes

(medians: 2.70 and 2.41 h, respectively)

com-pared to non-bleeding indications (medians:

3.44 and 2.89 h, respectively) Therefore, the

duration of action may by shorter when rFVIIa

is used to control bleeding episodes The

average percentage of the preparation found inplasma was significantly lower after administra-tion of rFVIIa in a dose of 70µg/kg (42.7%)compared to doses of 17.5µg/kg (50.1%)

or 35µg/kg (49.0%) (p = 0.0067) Additional

doses for specific patient populations are ranted however23,24 An increased eliminationrate and lower recovery of rFVIIa during bleed-ing may be related to consumption throughcomplex formation with TF exposed at the site

war-of vessel damage and on the phospholipidsexposed on the activated platelet surface The

volume of distribution at steady state (Vss), istwo to three times that of plasma and similar tothe half-life of recombinant factor VIIa24

MECHANISM OF HEMOSTATIC ACTION OF rFVIIa (see Figure 3)

Recombinant factor VIIa induces hemostasis atthe site of injury The mechanism of action

235

Figure 1 Three-dimensional molecular structure of factor VII Reproduced with permission from NovoNordisk

Trang 14

includes the binding of factor VIIa to the

exposed tissue factor-dependent pathway and,

independently of tissue factor, activation of

factor X directly on the surface of activated

platelets localized to the site of injury25,26

The formation of the TF/FVIIa or TF/

rFVIIa complex at the site of injury is necessary

to initiate hemostasis TF is a membrane-bound

glycoprotein, which normally is expressed on

cells in the subendothelium and is only exposed

following injury Tissue injury disrupts theendothelial cell barrier that normally separatesTF-bearing cells from the circulating blood.Once exposed to the blood, TF serves as ahigh-affinity receptor for FVIIa FVIIa is found

in the circulation, comprising about 1% of thetotal circulating FVII protein mass in theplasma It is endowed with very weak enzymaticactivity, which only becomes fully realized uponbinding to its cofactor, TF, at a site of vascularinjury25,26 Factor VIIa alone shows very littleproteolytic activity, only attaining its fullenzymatic potential when complexed to TF

In studies using TF incorporated into lipidvesicles, van’t Veer and colleagues demon-strated that zymogen FVII acts as an inhibitor

of FVIIa:TF-initiated thrombin generation.The addition of FVIIa at a concentration of

10 nmol/l in hemophilic conditions overcomesthis inhibition and results in a thrombin genera-tion equivalent to normal These data suggestthat the therapeutic effect of rFVIIa is due inpart to its ability to overcome the inhibitoryeffect of physiologic FVII on FVIIa:TF-initiatedthrombin generation27

However, if TF is no longer available orexposed to the clotting factors in the blood-stream, e.g when a platelet plug covers the TF-containing subendothelial space, or when TFactivity is inhibited by TFPI (tissue factor path-way inhibitor), then rFVIIa-mediated large-scale thrombin generation could take place onthe activated platelet surface independently of

TF28.The initial formation of a TF/FVIIa or TF/rFVIIa complex allows activation of FIX and

FX, and is crucial in generating the initial version of small amounts of prothrombin intothrombin (on the TF-bearing cells), which isessential to the amplification and propagationphase of coagulation FXa cannot move to theplatelet surface because of the presence of

con-236

Figure 2 The active two-chain enzyme factor

VIIa, is generated by specific cleavage AT Arg 152

Reproduced with permission from Novo Nordisk

Amino acid sequenceAmino acid compositionGamma-carboxylationPeptide map

Biological activityCarbohydrate composition

identicalidenticalidenticalidenticalidenticalsimilar

Table 1 Recombinant vs plasma-derived FVIIa21

Trang 15

normal plasma inhibitors, but instead remains

on the TF-bearing cell and activates a small

amount of thrombin Thrombin leads to the

activation of platelets and FV and FVIII at the

site of injury

This small amount of thrombin is not

suffi-cient for fibrinogen cleavage, but is critical for

hemostasis, as it can activate platelets, activate

and release FVIII from von Willebrand factor

(vWF) or activate platelet and plasma FV, and

FXI FIXa moves to the platelet surface, where

it forms a complex with FVIIIa and activates

FX on the platelet surface The activated

platelets provide for further thrombin tion Platelet-surface FXa is relatively protectedfrom normal plasma inhibitors and can complexwith platelet-surface FVa, where it activatesthrombin in quantities sufficient to provide forfibrinogen cleavage

genera-FIXa, FVIIIa and FVa bind efficiently to thesurface of the activated platelet and further acti-vation of FX into FXa occurs via the complexbetween FIXa and FVIIIa During amplifica-tion, FXa complexes with FVa to generatethrombin and subsequently activate FV, FVIIIand platelets

Trang 16

At pharmacological concentrations

(supra-physiological doses), rFVIIa also directly

activates FX on the surface of locally activated

platelets, helping to generate thrombin and

fibrin (platelet-dependent TF-independent

pathways) rFVIIa does not bind to resting

platelets Instead, the effect of high-dose rFVIIa

(which only activates FX on activated platelets)

is localized to the sites of vessel injury where TF

is exposed and platelets are activated29,30 This

results in the conversion of prothrombin into

large amounts of thrombin The full thrombin

burst mediated by FXa in complex with FVa is

necessary for the formation of a fully stabilized

and solid fibrin hemostatic plug

rFVIIa works by producing a stable fibrin

clot directly at the site of vascular injury, both

dependently and independently of TF This

reaction provides an extremely strong activation

of thrombin at the site of tissue damage, leading

to the formation of a stable fibrin network

Administration of rFVIIa might result in

forma-tion of a more stable hemostatic plug by a

variety of mechanisms, including enhancement

of activation of thrombin activatable fibrinolysis

inhibitor31, improvement of the physical

prop-erties of the fibrin clot, enhancement of platelet

activation32, and possibly enhancement of

FXIII activation

Lisman and colleagues observed that the

enhanced thrombin generation from FVIIa not

only accelerates clot formation, but also inhibits

fibrinolysis by activation of thrombin activatable

fibrinolytic inhibitor (TAFI) in factor

VIII-deficient plasma28 rFVIIa binding to

thrombin-activated platelets provides extra thrombin and

thus ensures both full activation of TAFI and

FXIII, and the formation of a dense fibrin

struc-ture The full thrombin burst generated

con-verts fibrinogen into a firm plug that is resistant

to premature lysis, thereby facilitating full

hemostasis

MONITORING THE CLINICAL EFFECT

OF rFVIIa

Currently, there is no good and/or satisfactory

laboratory method for monitoring the clinical

effectiveness of rFVIIa Administration of

rFVIIa results in shortening of the prothrombin

time (PT) and the activated partial plastin time (APTT) The PT generally short-ens to around 7–8 s except in FV- orFX-deficient plasma, suggesting that patientscompletely deficient in FV and/or FX will notbenefit from therapy with this product33 PTmay not adequately reflect coagulation func-tion The APTT shortening is due to the directactivation of FX by circulating FVIIa on thephospholipids used in the partial thrombo-plastin time test Data indicate that clinicalimprovement during rFVIIa treatment is associ-ated with a shortening of APTT of 15–20 s33.Post-rFVIIa coagulation parameters normalize

thrombo-as early thrombo-as 20 min after infusion Thus, theshortening of these two screening tests ofcoagulation does not necessarily reflect clinicaleffectiveness, which is judged subjectively.Coagulopathy is usually easy to recognize

by the clinical assessment of ongoing bleeding,physical examination and observation of oozingfrom cut surfaces, intravascular catheter sites

or mucus membranes The initial evaluationduring hemorrhage includes the PT, APTT,thrombin time (TT) and fibrinogen concentra-tion, antithrombin and platelet count In theinterpretation of these tests, it is important toknow the normal range and to be aware of thesensitivity of the screening tests for each coagu-lation factor, as these vary from laboratory

to laboratory In addition, assays of clottingparameters may provide different results withdifferent reagents, although these parameters donot show a direct correlation to the level ofhemostasis achieved Finally, it is important toremember that laboratory coagulation para-meters may be used as an adjunct to theclinical evaluation of hemostasis for monitoringthe effectiveness and treatment schedule ofrFVIIa34

Clotting parameters obtained prior to rFVIIaadministration are often outside the normalrange, perhaps indicating the development

of dilutional or consumption coagulopathy inthese patients Post rFVIIa, clotting parametersimprove, but do not normalize, and thus cannot

be used as predictors of rFVIIa efficacy

Laboratory monitoring of the efficacy ofrFVIIa treatment is helpful The effect on PT

is particularly marked, but this does notalways translate to clinically improved blood

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coagulation Similarly, measurement of the level

of FVII in plasma does not correlate with

clini-cal efficacy Study of the effects of rFVIIa on

monitoring plasma FVIIa levels demonstrates a

linear relationship between the concentration of

FVIIa and FVII:C (functional clotting ability),

but the therapeutic concentration range for

FVIIa has not yet been established The use of

plasma VIIa levels is controversial, and is not an

assay that is widely available

Levels of functional fibrinogen and

antithrombin do not change during repeated

injections of rFVIIa for the treatment of

hemor-rhage The minimal changes that occur

post-operatively are not greater than those seen with

patients who do not have coagulation disorders

Nonetheless, it is still advisable to monitor

patients at risk of systemic activation

Telgt and colleagues showed that low

concentration of rFVIIa, in the absence of TF,

can activate FX as assayed by the PT33,35

Higher concentration of rFVIIa had no

addi-tional effect on the PT At rFVIIa doses well

below the clinically therapeutic dose, a

maxi-mum shortening of the PT occurs Thus, at

doses in the clinically therapeutic range, no

fur-ther effect on the PT is observed This suggests

that, at concentrations typical for clinical use,

tests based on the PT are not useful for

monitoring the effect of rFVIIa Telgt and

colleagues, in an experimental study, observed

that rFVIIa effectively reduced PT and APTT

in normal and deficient (FVIII, FIX, FXI,

FXII) plasma This reduction of both

para-meters (PT and APTT) has been attributed to

the ability of rFVIIa to directly activate FX,

even in the absence of TF34,35

The best available indicator of rFVIIa

efficacy is the arrest of hemorrhage judged

by visual evidence, hemodynamic stabilization

and reduced demand for blood components36

There is currently no satisfactory laboratory test

to monitor the clinical effectiveness of rFVIIa

SAFETY OF rFVIIa

The complex coagulopathy and high

complica-tion rates seen in patients with intractable

postpartum hemorrhage, together with the

understanding of the localized mechanism

of action of rFVIIa, and the low risk

of thromboembolic complications followingadministration of the drug both in animal mod-els and in clinical use, all suggest that rFVIIa is auseful adjunctive therapy for control of severepostpartum hemorrhage Recombinant FVIIa is

a manufactured product, does not contain anyhuman plasma components, and therefore isfree from viral contamination Neither albuminnor any other human protein is used in its man-ufacturing process This means that there is norisk of transmission of human viruses or prions.Strict quality control standards are applied tothe fermentation process as well as the subse-quent extensive purification measures Geneticrecombination eliminates the dependency ondonors and allows for the production ofunlimited amounts of the medication20

Safety analyses demonstrate that rFVIIa

is associated with very few treatment-relatedadverse events and is very well tolerated Thus,experience with recombinant factor VIIa inseveral thousand patients has shown that theincidence of non-serious adverse events is 13%and serious adverse events are less than 1%37.Aledort calculated that the risk of rFVIIa-related thrombosis is 25 per 105 infusions38.Despite the mechanism of action, use of rFVIIa

in DIC and sepsis remains controversial eral reports suggest that rFVIIa may be usedsafely in such situations, without induction ofthrombotic complications or when conventionalreplacement therapy with fresh frozen plasmaand red blood cell concentrates fails to provide ahemostatic response Non-serious side-effectsare rarely seen during treatment with recombi-nant factor VIIa; the most common being pain

Sev-at the infusion site, fever, headache, vomiting,changes in the blood pressure and skin-relatedhypersensitivity reactions Adverse events havenot been related to dose

OUR EXPERIENCE

Between 2000 and 2006 in the Department

of Gynecology and Obstetrics, University ofMedical Sciences, Poznan we used rFVIIa inalmost 45 cases of postpartum hemorrhage39–46.According to data gathered from other areas ofPoland, we estimate that it has been used

in approximately 100 cases of postpartumhemorrhage

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The data presented below concern our first

18 patients in whom rFVIIa was used Detailed

information is presented in Tables 2–5 Our

patient data were obtained when we were using

a study protocol and were prepared to use the

drug This was not always the case in other

centers (see Table 6)

Recombinant FVIIa was administered venously at doses of 16.6–48µg/kg In mostcases, single administration of rFVIIa was suffi-cient However, in severe coagulopathy coexist-ing with postpartum hemorrhage or prolongedperiods of treatment (transfusions, complica-tions of shock) and recurrent bleeding, a seconddose similar to the initial dose was necessary tocontrol the bleeding

intra-Conclusions

The analysis of our data clearly shows thatrFVIIa was an effective hemostatic drug, whichsignificantly decreased bleeding and led to therapid stabilization of our patients’ conditions.Clearly, the early use of this agent decreases theamount of transfused preparations An impor-tant secondary observation was the contraction

of the uterus after the drug application inpatients who had qualified for hysterectomyshortly before the drug was administered Wesuggest that rFVIIa should be administered inevery case in which embolization of uterinearteries is being considered Coagulationparameters showed typical shortening of PTand APTT; however, the clinical effect – control

of bleeding – was the most important overalleffect of the drug There were no complications

of rFVIIa administration The dose, timing ofadministration after the diagnosis of postpartumhemorrhage, and the apparent ability toenhance uterine contractility will need furtherstudy in the future

WORLD-WIDE EXPERIENCE

Tables 6–8 present the world-wide experiencewith rFVIIa in obstetric hemorrhage Theresults reported in the literature support thebenefit of rFVIIa therapy in obstetric cases withmajor/life-threatening hemorrhage, even inthe presence of disseminated intravascularcoagulopathy (DIC)-like ‘coagulopathy’ Theydemonstrate that rFVIIa is highly effective andsafe in allowing quick arrest of life-threateningpostpartum hemorrhage unresponsive to con-ventional treatments Treatment with rFVIIaled to a reduction in the use of blood products

in this relatively large group of patients, ing blood product exposure for patients and

Genital tract trauma

Disseminated intravascular coagulation

Shock

81818Reoperations before rFVIIa administration

Obstetric hysterectomy*

72

*In six cases, hysterectomy was not performed

rFVIIa was administered after the decision to

oper-ate was made due to uncontrolled, life-threoper-atening

bleeding After its administration, the bleeding

stopped and the operation was not necessary In

two women, hysterectomy was performed in another

hospital, before the patients were transported to our

department

Table 2 Clinical details of patients with severe,

recurring and uncontrollable bleeding post-delivery

Before rFVIIa

After rFVIIa

3000 (1800–6800)0.00 (0–350)

Table 3 Blood loss before and after rFVIIa

U/P, units per patient

Table 4 Transfusion needed before and after

rFVIIa administration

Trang 19

sparing an expensive and limited resource.

Administration of rFVIIa should be also

con-sidered before hysterectomy and as an adjunct

to invasive/surgical procedures, before they are

undertaken This is particularly true in patients

who wish to preserve fertility

Conclusions

Randomized controlled studies are required to

determine the optimal dose and dose schedule

of rFVIIa for intractable postpartum hemorrhage

and to investigate whether the need for

hyster-ectomy/surgical procedures and overall

morbid-ity rates can be reduced by earlier treatment

with higher doses of rFVIIa In the meanwhile,

clinicians caring for acutely bleeding obstetric

patients should be aware of the potential of

rFVIIa to arrest life-threatening postpartum

hemorrhage Although an expensive product,

a trial of one to four doses of rFVIIa can be

justified in cases of uncontrolled bleeding which

persists despite maximal medical and surgical

treatment to achieve hemostasis

Although the limitations of anecdotal case

data are recognized, in the absence of efficacy

and safety data from randomized trials,

volun-tary registry submissions are being used to

pro-vide a preliminary insight into the scope of the

low incidence of clinical problems, as well as the

usefulness and adverse effects of this medication

when it is used ‘off-label’

rFVIIa dose

When a rationale for using rFVIIa was stated, it

was most commonly ‘last-resort’ therapy, after

other clinical measures had failed There was

no clear correlation between the severity ofbleeding and the dose of rFVII administered.Possibly the ‘timing’ determined the level of thedosing

Efficacy

Bleeding either stopped, markedly decreased

or decreased following rFVIIa administration in

54 of the cases In one patient, there was noresponse to therapy with rFVIIa Also only inone patient after an early significant reduction

of bleeding, recurrence was observed In eral, however, the rapid onset of action meansthat rFVIIa can be used in the perioperativeperiod There was no clear correlation betweenthe speed of response and either the type of pro-cedure performed, the severity of the bleedingcondition, or the dose of rFVIIa given

gen-Most patients continued to require someform of blood product replacement therapyduring the 24 h following rFVIIa administra-tion, but the need was greatly reducedcompared with the 24 h prior to rFVIIa admin-istration No correlation existed betweenbaseline and post-rFVIIa administration inlaboratory measurements and the predictability

of response to rFVIIa (data obtained fromreferences but not presented in tables) Further-more, of great importance, the results observed

in these tables of cases of postpartum rhage suggest that rFVIIa may be administeredeven in the presence of DIC-like ‘coagulo-pathy’ In the patients shown in Tables 6–8,major conditions reported to be associatedwith postpartum hemorrhage included some

hemor-241

Parameter

Normal range

Before rFVIIa

2 hours after rFVIIa

11.10(9.1–18.3)35.00(26–76)70.00(20–197)

11.25(9.1–17.6)36.80(22–69)69.50(19–186)

12.65(11.2–17.1)39.10(24–60)70.50(37–165)

PT, prothrombin time; APTT, activated partial thromboplastin time; PLT, platelets

Table 5 Selected laboratory tests before and after rFVIIa administration Data are given as median (range)

Tiêu đề	Acquired And Congenital Hemostatic Disorders
Trường học	University of Medicine
Chuyên ngành	Medicine
Thể loại	Bài báo
Năm xuất bản	2023
Thành phố	Hanoi

Định dạng
Số trang	50
Dung lượng	2,23 MB